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EP3160986A2 - Enveloppes du vih -1 doublement modifiées - Google Patents

Enveloppes du vih -1 doublement modifiées

Info

Publication number
EP3160986A2
EP3160986A2 EP15812422.2A EP15812422A EP3160986A2 EP 3160986 A2 EP3160986 A2 EP 3160986A2 EP 15812422 A EP15812422 A EP 15812422A EP 3160986 A2 EP3160986 A2 EP 3160986A2
Authority
EP
European Patent Office
Prior art keywords
seq
hiv
compri
composi
envel
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP15812422.2A
Other languages
German (de)
English (en)
Other versions
EP3160986A4 (fr
Inventor
Barton F. Haynes
Hua-Xin Liao
S. Munir Alam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Duke University
Original Assignee
Duke University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Duke University filed Critical Duke University
Publication of EP3160986A2 publication Critical patent/EP3160986A2/fr
Publication of EP3160986A4 publication Critical patent/EP3160986A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16071—Demonstrated in vivo effect
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates in general, to engineered, recombinantly produced HIV- 1 envelope and compositions comprising these envelopes, nucleic acids encoding these engineered envelopes, and various methods of use.
  • the present invention provides engineered, recombinantly produced HIV-1 envelopes and compositions comprising these envelopes.
  • the invention also provides methods of using these engi neered HIV-1 envel opes.
  • I n certai n embodi ments these composi ti ons are sui tabl e for use in inducing anti-HIV-1 antibodies.
  • immunogenic composi ti ons compri si ng envel ope protei ns and/or nucl ei c aci ds to i nduce cross-reacti ve neutralizing anti bodi es and i ncrease anti body breadth of coverage.
  • embodiments include methods of inducing broadly neutralizing anti-HIV-1 anti bodies using the inventive compositions, in any suitable immunization regimen.
  • the invention provides an engineered HIV-1 envelope of Figure !
  • the invention provides a double engineered HIV-1 envelope of SEQ ID NO: 1
  • theenvelope isrecombinantly produced in any suitable eel Is line, including but not limited to CHO cells.
  • the envel ope i s a monomer.
  • nucleic acid comprising a sequence encoding the envel ope of SEQ ID NO: 2, 4, 6, 8 or 10. In certain embodiments, the nucleic acid isof SEQ ID NO: 1, 3, 5, 7, or 9.
  • the invention provi des a composition comprising the double engi neered envel ope of the i nventi on.
  • the i nventi on provi des a composi ti on compri si ng a nucl ei c aci d encodi ng the doubl e engi neered envel ope of the i nventi on.
  • the composition is a pharmaceutical composition comprising any suitable career, excipient, adjuvant and thelike.
  • I n certai n aspects the i nventi on provi des a method of i nduci ng an i mmune response i n asubject comprising administering to the subject a composition compri sing any of the engi neered envel opes of the i nventi on, or nucl ei c aci d encodi ng these, i n an amount suffi ci ent to i nduce an i mmune response.
  • these envel opes are suitable for usein inducing anti-HIV-1 anti bodi es.
  • I n certai n em bodi ments these i mmunogeni c composi ti ons compri si ng envel ope proteins and/or nucleic acids are used to induce cross-reactive neutralizing antibodies and increase breadth of coverage.
  • the i nventi on al so rel ates to methods of i nduci ng such broadl y neutralizing anti-HIV-1 antibodies using such compositions.
  • Figure 1 shows nucleic acid and amino acid sequences of double engineered envel opes compri si ng del ta N-termi nal del eti on and V 3 cl eavage resi stant sequence.
  • the capitalized nucleotides depicted in SEQ I D NOS: 1, 3, 5 : 7, and 9 correspond to coding regions, respectively.
  • Figure 2 shows Clade B Engineered Env B63521 grown in CHO cells: SEC profile showing monomeric gp120.
  • Fi gure 3 shows CI ade B engineered Env B63521 gp120 grown in CHO cells: CD4 binding and CDi epitope upregulation.
  • the invention provides HIV- 1 engineered envelope proteins, or a functional fragment thereof, which comprise a sequence that prevents cleavage of the envel ope associated with recombinant expression in cells, e.g. CHO cells, and N-termi nal deletion which improves envel ope expression as a monomer.
  • the present invention provides engi neered HIV-1 envel ope proteins suitable for a I arge seal e recombi nant expressi on, e.g. but not I i mited i n a CHO eel 1 1 i ne.
  • the double engi neered proteins are purified and are suitable for use in in vitro and in vivo studies, including clinical trials
  • an HIV envelope designed in accordance with the present invention involves del eti on of residues (e.g., 5-11, 5, 6, 7, 8, 9, 10, or 11 amino acids) at the N-terminus.
  • residues e.g., 5-11, 5, 6, 7, 8, 9, 10, or 11 amino acids
  • amino acid residues ranging from 4 residues or even fewer to 14 residues or even more are deleted. These residues are between the maturation (signal peptide, usually ending with CX, X can beany amino acid) and
  • VFVXXXX "VFVXXX".
  • all amino acids between the maturation (signal peptide, usually ending with CX, X can beany ami no acid) and "VFVXXXX" sequence are del eted.
  • Envel opes were engineered by eliminating cleavageof recombinant HIV-I Envs produced, for example, in DHFR-deficient CHO cells. Most of HIV -1 gp 120 proteins expressed i n CHO eel I s are el eaved, whi I e the same gp120 protei ns expressed i n H EK293
  • eel Is are produced as intact proteins
  • HIV-I B.63521 gp140 Env proteins are produced as cleaved forms i n CHO eel Is, whi I e the same gp 140 protei ns express as i ntact proteins in HEK293 cells.
  • SDS-PAGE the cleaved HIV -1 Env proteins produced in CHO eel Is appear as intact proteins under non- reducing conditions, however, they mi grate as ⁇
  • TRPN N NTRKSI Rl GPGQTFY ATGD 11 GN I RQA H was used to modify HIV -1 envelopes, for example gp 120, gp140 or gp160 envelopes, so as to render them resistant to cleavage when produced in CHO eel Is (referred to as"mutC", see Figure 1).
  • the V31 oop sequence from any cl ade C envel ope can be used to create mutC compri si ng envelopes.
  • the properties of the double engineered envelopes of the invention including but not limited to immunogenicity, antigenicity, solubility, etc. can be characterized in any other suitable assays, including but not limited to assays as descri ed herein.
  • compositions and methods include any immunogenic H I V- 1 sequences to gi ve the best coverage f or T eel I hel p and cytotoxi c T eel I i nducti on.
  • the mosai c genes are any sui tabl e gene from the H I V - 1 genome.
  • the mosaic genes are Env genes, Gag genes, Pol genes, Nef genes, or any combination thereof. Seee.g. US Patent No. 7951377.
  • the mosaic genes are bi val ent mosai cs.
  • the mosai c genes are tri val ent.
  • the mosaic genes are administered in a sui table vector with each immunization wi th Env gene i nserts i n a suitabl e vector and/or as a protei n.
  • the mosaic genes for example as bivalent mosaic Gag group M consensus genes, are administered in a suitable vector, for example but not limited to HSV2, would be admi ni stered wi th each immunization wi th Env gene i nserts i n a sui tabl e vector, for exampl e but not limited to HSV-2.
  • Various methods for production and puri f i cati on of recombi nant protei ns sui tabl e f or use i n i mmuni zati on are known i n the art.
  • the immunogenic envelopes can also be administered as a protein boost in combination with avariety of nucleicacid envelope primes (e.g., HIV-1 Envs delivered as DNA expressed in viral or bacterial vectors).
  • nucleicacid envelope primes e.g., HIV-1 Envs delivered as DNA expressed in viral or bacterial vectors.
  • Nucleoti de-based vaccines offer a flexible vector format to immunize against virtually any protein antigen.
  • twotypesof genetic vaccination are avail able for testing— DNAsand mRNAa
  • DNA can be delivered as naked DNA.
  • DNA is f ormulated for del i very by a gene gun.
  • I n certai n embodi ments, D N A i s admi ni stered by electroporation, or by a needle-free injection technologies, for example but not limited to Biojector® device.
  • the DNA is inserted in vectors.
  • the DNA is del i vered usi ng a sui tabl e vector for expressi on i n mammal i an eel I s.
  • certai n embodi ments the nucl ei c aci ds encodi ng the envel opes are opti mi zed for expressi on.
  • certai n embodi ments the nucl ei c aci ds encodi ng the envel opes are opti mi zed for expressi on.
  • DN A isoptimized, e.g. codon optimized, for expression.
  • the nucleic acids are opti mi zed for expression in vectors and/or in mammalian cells
  • these are bacterially derived vectors, adenovirus based vectors, rAdenovirus(Barouch DH, et al. Nature Med. 16: 319-23, 2010), recombinant mycobacteria (i.e., rBCG or M smegmatis) (Yu, JS et al. Clinical Vaccine Immunol . 14: 886-
  • V virology 85: 9854-62, 2011) NYVAC, modified vaccinia Ankara (MVA)), adeno-associated vi rus, consuel an equi ne encephal i ti s (V EE) repl i cons, Herpes Si mpl ex V i rus vectors, and other suitable vectors.
  • DNA or RNA i s administered as nanoparticles consisting of low dose antigen-encoding DNA formulated with a block copolymer (amphiphilic block copolymer 704). See Cany et al ., Journal of Hepatology 2011 vol.
  • Nanocarrier technologies called Nanotaxi® for immunogenic macromolecules (DNA, RNA, Protein) delivery are under development. See for example technologies developed by In-cellart. [0025] Dosing of proteins and nuclei c acids can be readily determined by a ski I led artisan.
  • a single dose of nucleic acid can range from afew nanograms(ng) to afew micrograms (3 g) or milligram of a single immunogenic nucleic acid.
  • Recombinant protein dose can range from a few 3 g mi crograms to a few hundred mi crograms, or mi 11 i grams of a si ngl e i mmunogeni c polypeptide.
  • compositions can be formulated with appropriate carriers using known techni ques to yi el d composi ti ons sui tabl e for vari ous routes of admi ni strati on .
  • the composi ti ons are del i vered vi a i ntramascul ar ( I M ), vi a
  • the composi ti ons can be formulated with appropri ate carriers and adjuvants using techni ques to yield compositionssuitablefor immunization.
  • the compositions can include an adjuvant, such as, for example but not limited to, alum, poly IC, M F-59 or other squalene- based adjuvant, ASOIB, or other liposomal based adjuvant sui table for protein or nucleic acid immunization.
  • TLR agonists are used asadjuvants.
  • adj uvants whi ch break i mmune tol erance are i ncl uded i n the i mmunogeni c compositions.
  • BnAb knock-in mouse models are provi di ng i nsi ghts i nto the vari ous mechani sms of tol erance control of M FER BnAb induction (deletion, anergy, receptor editing).
  • compositions and methods of theinvention can be used in combination with any agent and method to reducing the effects of host tolerance controls in the production of HIV-1 bnAbs.
  • the embodi ments of the present disclosure can be embodied i n forms other than those sped fically disci osed above.
  • the parti cul ar embodi ments descri bed herei n are, therefore, to be consi dered as i 11 ustrati ve and not restri cti ve.
  • Those ski 11 ed i n the art wi 11 recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the sped f i c embodi ments descri bed herei n.
  • thescopeof theinvention is not limited to specific embodiments di scl osed i n these [Exampl es, whi ch are for purposes of i 11 ustrati on onl y , si nee al ternati ve methods can be uti I i zed to obtai n si mi I ar resul ts.
  • Fi gure 2 shows that the envel ope i s expressed as a monomer.
  • Fi gure 2 shows chromatography profileof aCHO expressed and purified protein.
  • the antigenicity of double engineered gp120 envelope B63251 was determined in an antibody binding assay.
  • Figure 3 shows that the double engi neered gp120 envelope B63251 i s expressed as a monomer and retains its properties, as demonstrated by its binding to 17B, which isaCD4 binding site antibody.
  • the invention provide an immunization regimen with ALVAC-HIV VFC1521 primeX2 then ALVAX vPC1521 boost X2 with A244 gp 120 Delta 11 +B.63521 Delta 11 gp120+ AA 104.0 delta 11 or 7 gp120 + AA 107.0 del ta11 or 7gp 120 + AA058.1 delta 11 or 7 gp120.
  • An alternate set of AA Envs is AA072.I , AA009.1 , and AA015.1. See WO 2014/17235 at Fi gures 1 , 5, 6.
  • thegp120 envelopes are double engineered to include deltaN del eti on and mutC change as descri bed herei n, for exampl e i n Fi gure 1.
  • a A Envs whi oh are deltaN mutC envelopes can be engineered from the sequences in WO 2014/17235 at Figures 1, 5, 6.
  • Group A bivalent boost
  • ALVAC vFC1521 primeX2 ALVACVPC1521 + B/E boost X2 (B.6240 gp120D11 + A244 gp120 D11 in GLA/SE), or optionally
  • VFC1521 + B/E boost X2 (B.63521 qp120D11 + A244 qp120 D11 in GLA/SE)
  • Group C pentavaJent boost
  • ALVAC VFC1521 + B/E boost X2 (B.6240 qp120D11 + A244 gp120 D11 + new three valent AE gp120s in GLA/SE)— new trivaJent gp120s include: AA104.0 delta 11 or 7 gp120 + AA107.0 deltal 1 or 7gp 120 + AA058.1 delta 11 or 7 gp120.
  • Group D penentavalent boost
  • ALVAC VPC1521 + B/E boost X2 B.63521 qp120D11 + A244 gp120 D11 + new three valent AE gp120s in GLA/SE
  • new trivaJent gp120s include: AA104.0 delta 11 or 7 gp120 + AA107.0 deltal 1 or 7gp 120 + AA058.1 delta 11 or 7 gp120.
  • a E SH IV low dose rectal challenge -the AE SHIV could be either SHIV AE16 or SHIV1157 tier 2 Y173H.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Mycology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne, dans certains aspects, des protéines d'enveloppe du VIH -1 modifiées et leurs utilisations. Les enveloppes modifiées comprennent une séquence qui empêche le clivage de l'enveloppe associé à l'expression de recombinaison dans une lignée cellulaire, et une délétion de N-terminale qui améliore l'expression de l'enveloppe en tant que monomère.
EP15812422.2A 2014-06-25 2015-06-25 Enveloppes du vih -1 doublement modifiées Withdrawn EP3160986A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462016792P 2014-06-25 2014-06-25
PCT/US2015/037754 WO2015200673A2 (fr) 2014-06-25 2015-06-25 Enveloppes du vih -1 doublement modifiées

Publications (2)

Publication Number Publication Date
EP3160986A2 true EP3160986A2 (fr) 2017-05-03
EP3160986A4 EP3160986A4 (fr) 2018-05-16

Family

ID=54938938

Family Applications (1)

Application Number Title Priority Date Filing Date
EP15812422.2A Withdrawn EP3160986A4 (fr) 2014-06-25 2015-06-25 Enveloppes du vih -1 doublement modifiées

Country Status (4)

Country Link
US (1) US20180036400A1 (fr)
EP (1) EP3160986A4 (fr)
CA (1) CA2953150A1 (fr)
WO (1) WO2015200673A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2017221379A1 (en) 2016-02-16 2018-08-16 Geovax Inc. Multivalent HIV vaccine boost compositions and methods of use

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2790426A1 (fr) * 2010-02-18 2011-08-25 Emory University Vecteurs exprimant des antigenes du vih et le gm-csf et procedes associes destines a generer une reponse immunitaire
EP2588211A4 (fr) * 2010-06-30 2014-03-05 Torrey Pines Inst Immunogènes trimères d'env
EP2739300B1 (fr) * 2011-07-05 2019-06-19 Duke University Immunogènes gp120 à extrémité n-terminale délétée
WO2013085550A2 (fr) * 2011-12-05 2013-06-13 Duke University Immunogènes v1v2
WO2014165494A1 (fr) * 2013-04-02 2014-10-09 Duke University Production de glycoprotéines d'enveloppe du vih-1 par des techniques de recombinaison
WO2014172335A1 (fr) * 2013-04-15 2014-10-23 Duke University Immunogène du vih -1 polyvalent
EP3049524A4 (fr) * 2013-09-27 2017-06-14 Duke University Corrélats de protection contre une transmission de mère à enfant du vih-1, et vaccin

Also Published As

Publication number Publication date
WO2015200673A3 (fr) 2016-03-24
WO2015200673A2 (fr) 2015-12-30
WO2015200673A9 (fr) 2016-05-19
US20180036400A1 (en) 2018-02-08
EP3160986A4 (fr) 2018-05-16
CA2953150A1 (fr) 2015-12-30

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